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Figure 1.
Flowchart of Article Search and Inclusion
Flowchart of Article Search and Inclusion
Figure 2.
Likelihood in Patients With Melanoma of Positive Sentinel Lymph Node (SLN) Biopsy Findings
Likelihood in Patients With Melanoma of Positive Sentinel Lymph Node (SLN) Biopsy Findings

Illustrated are the standardized odds ratios (ORs) for the studies included in the meta-analysis. Patients with histologic regression of primary melanoma had a lower likelihood of SLN positivity (OR, 0.56; 95% CI, 0.41-0.77; darker dashed vertical line) than patients without regression.

Figure 3.
Likelihood of Positive Sentinel Lymph Node (SLN) Biopsy Findings in Patients With Melanoma by Study Quality
Likelihood of Positive Sentinel Lymph Node (SLN) Biopsy Findings in Patients With Melanoma by Study Quality

Illustrated are the standardized odds ratios (ORs) for the high- and low-quality studies included in the meta-analysis. Patients with regression enrolled in high-quality studies had a lower likelihood of SLN positivity (OR, 0.48; 95% CI, 0.32-0.72; darker dashed vertical line) than similar patients enrolled in low-quality studies (OR, 0.73; 95% CI, 0.0.53-1.00; darker dashed vertical line).

Figure 4.
Funnel Plot of the Studies Included in the Meta-analysis
Funnel Plot of the Studies Included in the Meta-analysis

The funnel plot displays points (each representing an included study) that are evenly and symmetrically distributed, thus showing the absence of study bias and suggesting that the results of the studies are reliable. Ln indicates natural log; OR, odds ratio; SE, standard error.

Table.  
Characteristics of the Included Studies
Characteristics of the Included Studies
1.
Kang  S, Barnhill  RL, Mihm  MC  Jr, Sober  AJ.  Histologic regression in malignant melanoma: an interobserver concordance study. J Cutan Pathol. 1993;20(2):126-129.
PubMedArticle
2.
Requena  C, Botella-Estrada  R, Traves  V, Nagore  E, Almenar  S, Guillén  C.  Problems in defining melanoma regression and prognostic implication [in Spanish]. Actas Dermosifiliogr. 2009;100(9):759-766.
PubMedArticle
3.
Blessing  K, McLaren  KM.  Histological regression in primary cutaneous melanoma: recognition, prevalence and significance. Histopathology. 1992;20(4):315-322.
PubMedArticle
4.
Ribero  S, Osella-Abate  S, Sanlorenzo  M,  et al.  Favourable prognostic role of regression of primary melanoma in AJCC stage I-II patients. Br J Dermatol. 2013;169(6):1240-1245.
PubMedArticle
5.
Morton  DL, Cochran  AJ, Thompson  JF,  et al; Multicenter Selective Lymphadenectomy Trial Group.  Sentinel node biopsy for early-stage melanoma: accuracy and morbidity in MSLT-I, an international multicenter trial. Ann Surg. 2005;242(3):302-311.
PubMed
6.
Lourari  S, Paul  C, Gouraud  PA,  et al; Skin Oncology Working Group of the Société Française de Dermatologie (French Society of Dermatology).  Sentinel lymph node biopsy for melanoma is becoming a consensus: a national survey of French centres involved in melanoma care in 2008. J Eur Acad Dermatol Venereol. 2012;26(10):1230-1235.
PubMedArticle
7.
Kaur  C, Thomas  RJ, Desai  N,  et al.  The correlation of regression in primary melanoma with sentinel lymph node status. J Clin Pathol. 2008;61(3):297-300.
PubMedArticle
8.
Socrier  Y, Lauwers-Cances  V, Lamant  L,  et al.  Histological regression in primary melanoma: not a predictor of sentinel lymph node metastasis in a cohort of 397 patients. Br J Dermatol. 2010;162(4):830-834.
PubMedArticle
9.
Morton  DL, Thompson  JF, Cochran  AJ,  et al; MSLT Group.  Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370(7):599-609.
PubMedArticle
10.
Ribero  S, Osella-Abate  S, Sanlorenzo  M,  et al.  Sentinel lymph node biopsy in thick-melanoma patients (N=350): what is its prognostic role? Ann Surg Oncol. 2015;22(6):1967-1973.
PubMedArticle
11.
Shaw  HM, McCarthy  SW, McCarthy  WH, Thompson  JF, Milton  GW.  Thin regressing malignant melanoma: significance of concurrent regional lymph node metastases. Histopathology. 1989;15(3):257-265.
PubMedArticle
12.
White  RL  Jr, Ayers  GD, Stell  VH,  et al; Sentinel Lymph Node Working Group.  Factors predictive of the status of sentinel lymph nodes in melanoma patients from a large multicenter database. Ann Surg Oncol. 2011;18(13):3593-3600.
PubMedArticle
13.
Balch  CM, Gershenwald  JE, Soong  SJ,  et al.  Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27(36):6199-6206.
PubMedArticle
14.
Wong  SL, Balch  CM, Hurley  P,  et al; American Society of Clinical Oncology; Society of Surgical Oncology.  Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline. J Clin Oncol. 2012;30(23):2912-2918.
PubMedArticle
15.
Panic  N, Leoncini  E, de Belvis  G, Ricciardi  W, Boccia  S.  Evaluation of the endorsement of the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement on the quality of published systematic review and meta-analyses. PLoS One. 2013;8(12):e83138.
PubMedArticle
16.
Prictor  M, Hill  S.  Cochrane Consumers and Communication Review Group: leading the field on health communication evidence. J Evid Based Med. 2013;6(4):216-220.
PubMedArticle
17.
Kuller  LH, Goldstein  BD.  Suggestions for STROBE recommendations. Epidemiology. 2007;18(6):792-793.
PubMedArticle
18.
Han  D, Zager  JS, Shyr  Y,  et al.  Clinicopathologic predictors of sentinel lymph node metastasis in thin melanoma. J Clin Oncol. 2013;31(35):4387-4393.
PubMedArticle
19.
Botella-Estrada  R, Traves  V, Requena  C, Guillen-Barona  C, Nagore  E.  Correlation of histologic regression in primary melanoma with sentinel node status. JAMA Dermatol. 2014;150(8):828-835.
PubMedArticle
20.
Grotz  TE, Vaince  F, Hieken  TJ.  Tumor-infiltrating lymphocyte response in cutaneous melanoma in the elderly predicts clinical outcomes. Melanoma Res. 2013;23(2):132-137.
PubMedArticle
21.
Testori  A, De Salvo  GL, Montesco  MC,  et al; Italian Melanoma Intergroup.  Clinical considerations on sentinel node biopsy in melanoma from an Italian multicentric study on 1,313 patients (SOLISM-IMI). Ann Surg Oncol. 2009;16(7):2018-2027.
PubMedArticle
22.
Gutzmer  R, Satzger  I, Thoms  KM,  et al.  Sentinel lymph node status is the most important prognostic factor for thick (> or = 4 mm) melanomas. J Dtsch Dermatol Ges. 2008;6(3):198-203.
PubMedArticle
23.
Morris  KT, Busam  KJ, Bero  S, Patel  A, Brady  MS.  Primary cutaneous melanoma with regression does not require a lower threshold for sentinel lymph node biopsy. Ann Surg Oncol. 2008;15(1):316-322.
PubMedArticle
24.
Topping  A, Dewar  D, Rose  V,  et al.  Five years of sentinel node biopsy for melanoma: the St George’s Melanoma Unit experience. Br J Plast Surg. 2004;57(2):97-104.
PubMedArticle
25.
Wagner  JD, Gordon  MS, Chuang  TY,  et al.  Predicting sentinel and residual lymph node basin disease after sentinel lymph node biopsy for melanoma. Cancer. 2000;89(2):453-462.
PubMedArticle
26.
Tejera-Vaquerizo  A, Nagore  E, Herrera-Acosta  E,  et al.  Prediction of sentinel lymph node positivity by growth rate of cutaneous melanoma. Arch Dermatol. 2012;148(5):577-584.
PubMedArticle
27.
Callender  GG, Egger  ME, Burton  AL,  et al.  Prognostic implications of anatomic location of primary cutaneous melanoma of 1 mm or thicker. Am J Surg. 2011;202(6):659-664.
PubMedArticle
28.
Mandalà  M, Imberti  GL, Piazzalunga  D,  et al.  Clinical and histopathological risk factors to predict sentinel lymph node positivity, disease-free and overall survival in clinical stages I-II AJCC skin melanoma: outcome analysis from a single-institution prospectively collected database. Eur J Cancer. 2009;45(14):2537-2545.
PubMedArticle
29.
Kruper  LL, Spitz  FR, Czerniecki  BJ,  et al.  Predicting sentinel node status in AJCC stage I/II primary cutaneous melanoma. Cancer. 2006;107(10):2436-2445.
PubMedArticle
30.
Liszkay  G, Orosz  Z, Péley  G,  et al.  Relationship between sentinel lymph node status and regression of primary malignant melanoma. Melanoma Res. 2005;15(6):509-513.
PubMedArticle
31.
Savoia  P, Fava  P, Caliendo  V,  et al.  Disease progression in melanoma patients with negative sentinel lymph node: does false-negative specimens entirely account for this phenomenon? J Eur Acad Dermatol Venereol. 2012;26(2):242-248.
PubMedArticle
32.
Ribero  S, Quaglino  P, Osella-Abate  S,  et al.  Relevance of multiple basin drainage and primary histologic regression in prognosis of trunk melanoma patients with negative sentinel lymph nodes. J Eur Acad Dermatol Venereol. 2013;27(9):1132-1137.
PubMedArticle
33.
Ma  MW, Medicherla  RC, Qian  M,  et al.  Immune response in melanoma: an in-depth analysis of the primary tumor and corresponding sentinel lymph node. Mod Pathol. 2012;25(7):1000-1010.
PubMedArticle
Original Investigation
December 2015

Association of Histologic Regression in Primary Melanoma With Sentinel Lymph Node StatusA Systematic Review and Meta-analysis

Author Affiliations
  • 1Section of Dermatology, Department of Medical Sciences, University of Turin, Turin, Italy
  • 2Section of Dermatologic Surgery, Department of Oncology and Hematology, Città della Salute e della Scienza di Torino Hospital, Turin, Italy
  • 3Department of Public Health, University of Turin, Turin, Italy
  • 4Section of Surgical Pathology, Department of Medical Sciences, University of Turin, Turin, Italy
JAMA Dermatol. 2015;151(12):1301-1307. doi:10.1001/jamadermatol.2015.2235
Abstract

Importance  The prognostic significance of regression in primary melanoma has been debated for many years. There is no consensus regarding the need for sentinel lymph node (SLN) biopsy when regression is present within the primary tumor.

Objective  To review the evidence that regression may affect SLN status.

Data Sources  A systematic review was performed by searching in MEDLINE, Scopus, and the Cochrane Library from January 1, 1990, through June 2014.

Study Selection  All studies that reported an odds ratio (OR) or data on expected and observed cases of SLN positivity and histologic regression were included.

Data Extraction and Synthesis  Primary random-effects meta-analyses were used to summarize ORs of SLN positivity and histologic regression. Heterogeneity was assessed using the χ2 test and I2 statistic. To assess the potential bias of small studies, we used funnel plots, the Begg rank correlation test, and the Egger weighted linear regression test. The methodologic quality of the studies was assessed according to the Strengthening of Reporting of Observational studies in Epidemiology (STROBE) checklist, and 2 different meta-analyses were performed based on those criteria.

Main Outcomes and Measures  Summary ORs of histologic regression of primary melanoma and SLN status.

Results  Of the 1509 citations found in the search, 94 articles were reviewed, and 14 studies comprising 10 098 patients were included in the analysis. In the combined 14 studies, patients with regression had a lower likelihood to have SLN positivity (OR, 0.56; 95% CI, 0.41-0.77) than patients without regression. On the basis of study quality, we found that patients with regression enrolled in high-quality studies had a lower likelihood to have SLN positivity (OR, 0.48; 95% CI, 0.32-0.72) compared with results of low-quality studies (OR, 0.73; 95% CI, 0.53-1.00). Examination of the funnel plot did not provide evidence of publication bias.

Conclusions and Relevance  The results of this analysis showed that the risk of SLN positivity was significantly lower in patients with histologic regression compared with those without. Regression may be used in these cases to make a selection of which patients should be the most appropriate for this procedure.

Introduction

Histologic regression in melanoma is defined as an area within the tumor in which neoplastic cells have disappeared or become reduced in number from the dermis (and occasionally from the epidermis) and have been substituted by fibrosis with accompanying melanophages, new vessels, and a variable inflammatory infiltrate.1,2 Regression is found in melanoma with a frequency that ranges from 10% to 35%.3 The prognostic significance of regression in primary melanoma has been debated for many years.4 The potential poor prognosis associated with regression is that the disappearance of a portion of the tumor may lead to an underestimation of the original Breslow thickness. It is therefore difficult to accurately assess prognosis and also whether sentinel lymph node biopsy (SLNB) should be used to assess thickness, since it might no longer be accurate.58

Sentinel lymph node (SLN) status is the most important prognostic factor in intermediate and thick melanomas.9,10 There is no consensus regarding the need for SLNB when regression is present within the primary tumor.

Some authors5,11 reported that regression is associated with a higher risk of developing lymph node metastasis. On the contrary, White et al12 reported that in thin melanomas (<1 mm), the presence of regression is associated with a lower likelihood of positive SLN findings. Furthermore, other studies have shown that regression does not increase the risk of metastases1,7 and does not negatively affect prognosis.4

A consensus survey carried out in France demonstrated that guidelines for most melanoma centers advocate SLNB in the case of Breslow thickness greater than 1.0 mm (76%) and/or ulceration of the primary melanoma (38%) and/or histologic regression of the primary melanoma (24%).6 Other countries do not have regression as a selection criteria for SLNB.

Since 2009, SLNB has been recommended for intermediate-thickness (1- to 4-mm) melanomas.13 However, it has recently been extended to thinner lesions showing mitosis.14 Given the lack of evidence-based guidelines by which to stratify thin melanomas for this procedure, the selection criteria in fact vary widely between institutions and countries. To review the evidence that regression may affect SLN status, we conducted a meta-analysis of published literature to provide a more objective estimate of the incidence of SLN positivity in patients with histologic regression in primary melanoma tumors.

Methods

We carried out this review in accordance with PRISMA (Preferred Reporting Items for Systematic review and Meta-analysis guidelines).15

Search Strategy, Eligibility Criteria, and Study Selection

A systematic review of original articles and abstracts analyzing the SLN status of patients with histologic regression of primary melanoma was performed by searching in MEDLINE, Scopus, and the Cochrane Library from January 1, 1990, through June 2014. The search strategy included the following keywords in various combinations: “melanoma,” “lymph nodes,” “sentinel lymph node biopsy,” “histologic regression”; 1509 citations were reported in total. In addition we reviewed articles and relevant reviews to locate publications missed by the database searches. Two authors (S.R. and E.B.) independently assessed the eligibility of studies. Any disagreement was settled by consensus, including a third and fourth investigator (S.O.-A. and P.Q.). The article title and abstract were used for initial screening, followed by review of the full text. There was no restriction criterion on the number of patients enrolled in the study. Only original manuscripts in English language were included. Searches were supplemented by scanning bibliographies of included articles. We excluded articles that reported no data, such as review articles and editorials. If duplicate data were present in separate publications, we included the publication with the larger amount of data or the more recent. All articles that reported data on SLN status and histologic regression in patients with melanoma were eligible for inclusion.

Data Extraction

We used a data extraction form based on the Cochrane Consumers and Communication Review Group data examination template.16 For each study selected, the following data were extracted: journal, year, study design, number of patients, age, sex, melanoma thickness, ulceration, histologic regression, SLN status.

Assessment of Study Quality

The quality of studies included in the meta-analysis, in terms of design, is of utmost importance because combining study results of poor quality may lead to biases and therefore misleading results. Study quality may be used for explaining the heterogeneity of the study outcomes; however, no consensus exists regarding the assessment of statistical analysis. For each article, study quality was determined by blinded review by 2 independent reviewers (S.R. and P.Q.). To avoid selection bias, no study was excluded based on the quality score alone in the assessment of the overall effect. The methodologic quality of the studies was assessed according to the Strengthening of Reporting of Observational Studies in Epidemiology (STROBE) checklist.17 The STROBE statement consists of a checklist of 22 items that should be addressed in reports of observational studies.

Statistical Analysis

To integrate previous findings on this topic, we performed a meta-analysis of published literature to provide an estimate of the incidence of SLN positivity in patients with melanoma with evidence of regression in the tumor. Because studies were found to be heterogeneous, summary odds ratios (ORs) with corresponding 95% CIs were calculated using random-effects modeling. Publication bias was assessed through the construction of a funnel plot for the primary end point, as well as with the Begg and Mazumdar adjusted rank correlation method. To address the heterogeneity of the studies, we therefore performed subgroup analyses by considering the quality of the studies assessed through the STROBE checklist. Nine studies scored more than 75% of the STROBE criteria,8,1825 while 5 studies fulfilled less than 75% of those criteria.2630

Statistical analyses were performed using Stata statistical software, version 13.0 (StataCorp LP).

Results
Characteristics of Included Studies

The initial search resulted in 1509 citations (Figure 1). The title and abstract of each retrieved publication was reviewed to confirm that the article included data on SLN positivity and regression melanoma tumors. In the event that this approach was not informative, the full article was retrieved and further reviewed. This process resulted in the selection of 94 studies. Of these, 74 were eventually excluded from this analysis because they did not showed clear results on SLN status in relation to regression. Five presented overlapping data from other studies so were also excluded. Fourteen studies8,1830 were therefore eligible for the inclusion in the systematic review and meta-analysis. Five of those reported data pooled from multiple centers (Table).18,21,22,26,27

Ultimately, 14 studies including a total of 10 098 patients were finally included. Sentinel lymph node inclusion criteria were clearly described in 9 studies.8,19,21,22,2630 From these 9 studies, regression was described as a selection criteria for SLNB in 4 of them.8,21,29,30 Histologic description of regression was reported in 7 articles.8,18,20,21,26,29,30 Presence of histologic regression in primary melanoma was reported in 10% to 51% of patients with negative SLNs and 35% or fewer with positive SLNs in 13 out of 14 studies8,1825,2730; only Tejera-Vaquerizo et al26 did not describe crude values of distribution but reported only the OR of this association with a confidence interval.

All studies reported clinical data of the patients on sex and age. Among them, data on Breslow thickness that is the major prognostic factor in melanoma, were described as mean depth in 4 studies22,25,28,30 and as median depth in 5.8,18,22,23,27 In the remaining 6 articles,1921,24,26,29 Breslow thickness was reported as categorical cutoff. Ulceration distribution was described in all 14 articles.8,1830 Of the 14 analyzed reports, seven8,20,23,2628,30 declared the association between histologic regression and other demographic data or tumor variables. In particular, Grotz et al20 showed that histologic regression was not associated with sex, age, Breslow thickness, ulceration, mitotic rate, satellitosis, or tumor-infiltrating lymphocytes. Tejera-Vaquerizo et al26 showed that a lower rate of histologic regression was associated with fast-growth melanoma. Liszkay et al30 demonstrated that tumors with histologic regression were associated to superficial spreading melanoma histotype, thinner lesions, and absence of ulceration. Also Socrier et al8 observed that only 2% of melanoma lesions presented both regression and ulceration. In consideration of primary anatomic site, regression was significantly associated with primary melanoma located on the trunk in 3 studies.23,27,30 In contrast, no significant association between anatomic site (trunk vs extremities) and regression was observed by Mandalà et al.28

Outcome of Meta-analysis

In the included 14 studies combined, patients with histologic regression of primary melanoma had a lower likelihood to have a SLN positivity (OR, 0.56; 95% CI, 0.41-0.77) than patients without regression (Figure 2). On the basis of study quality, we found that patients with regression enrolled in high-quality studies had a lower likelihood to have SLN positivity (OR, 0.48; 95% CI, 0.32-0.72) compared with those enrolled in low-quality studies (OR, 0.73; 95% CI, 0.53-1.00) (Figure 3 and Figure 4). Examination of the funnel plot (Figure 4) did not provide evidence of publication bias. Similarly, there was no evidence of such bias for the sensitivity analysis. In fact, the analysis shows that the points are evenly distributed and symmetrical, thus showing absence of bias and suggesting that the results of the studies are reliable. This evidence was confirmed by the results of the Begg and Mazumdar test (0.53 and 0.15 for the overall calculation for the high-quality studies and the low-quality studies, respectively; P = .75).

Discussion

In this systematic review and meta-analysis including 14 studies8,1830 and more than 10 000 patients, we found that histologic regression is a protective factor for SLN-positive status: patients with melanoma and regression had a lower likelihood of SLN positivity (OR, 0.56; 95% CI, 0.41-0.77) than patients without regression.

Clinical Significance

Histologic regression has traditionally been considered a marker of poor prognosis because it leads to an underestimation of melanoma thickness.58 The introduction of SLNB has led to the evaluation of melanoma tumor thickness and ulceration for the selection of patients eligible for SLNB, and regression is a feature that has previously been evaluated.5 Some studies have found that regression in melanoma does not increase the risk of lymphatic metastasis and therefore does not affect prognosis,7,25,30,31 while other studies have reported that regression is associated with a poor prognosis, particularly in thin melanomas.11 Our group has previously reported that regression plays a protective prognostic role in patients with melanoma (stage I-II AJCC).4,32

It can sometimes be difficult to decide if patients should undergo SLNB for tumors thinner than 1 mm.4,10 Although the presence of mitosis is now among the inclusion criteria for SLNB, adding regression may provide extra prognostic value. To our knowledge, the current report represents the first meta-analysis to focus on the predictive value of histologic regression on SLN status in melanoma. We found that the risk of sentinel metastatic involvement was significantly lower in patients with histologic regression in melanoma tumors compared with those without regression.

Conflicting data are reported on prognostic value of histologic regression. Kaur et al7 observed that SLN positivity was more common in tumors with regression than in those without. In contrast, Testori et al21 suggest that regression should be considered a protective factor for SLN metastasis. Mandalà et al28 did not observe any correlation between regression and SLN positivity. Similarly, Morris et al23 showed that the presence of histologic regression in a primary melanoma predicted neither SLN positivity stratified by the Breslow thickness nor increased the risk of recurrence when compared with melanomas without regression. Melanoma is a strong immunogenic tumor. A strong host immunological response to the tumor is thought to be the cause of the tumor regression. It would therefore be expected that the presence of regression would confer survival advantage.

Nevertheless, it can be suggested that a host immunologic response to the tumor could be the basis of regression. This phenomenon therefore could reflect the power of the immunologic system against the primary tumor, and its presence should be considered prognostically favorable. Ma et al33 showed that the immune profile of the primary melanoma could predict the SLN status and that the presence of primary tumor regression results from a T-cell immune response associated with a decreased risk of nodal progression. In particular, these authors describe a downregulation of the antitumor immunity in the positive SLN with an increase in regulatory T cells compared with the negative nonsentinel node from the same nodal basin. Furthermore, Ma et al33 reported that primary tumor conventional dendritic cells and regression were protective against SLN metastasis.

Limitations

Significant heterogeneity existed among studies with respect to study quality characteristics, as confirmed by the Q statistic. Although random-effect modeling incorporates this heterogeneity, the possibility remains that the SLN positivity rate in each study is mediated by unmeasured factors, and the pooled SLN positivity rate may be misleading as a result. We could not adjust our pooled estimate for the effects of confounding through a formal metaregression because covariate information was not consistently reported in the published studies. The reliability of summary estimates is contingent on the quality of the studies pooled. Despite this, when random effects were evaluated in 2 subgroups of studies divided by quality based on the STROBE test, the protective role of regression was maintained. We found that patients with regression enrolled in high-quality studies had a lower likelihood of SLN positivity (OR, 0.48; 95% CI, 0.32-0.72) than similar patient enrolled in low-quality studies (OR, 0.73; 95% CI, 0.0.53-1.00). Although included studies met many of the a priori quality metrics, important deficiencies remained. Because the indication for SLNB and the ultimate outcomes of those with a positive result is very hard to assess in a randomized fashion, methodologic shortcomings are inevitable.

Another potential limitation is that the included studies may have had different definitions of histological regression, as sometimes the definition of this feature is discussed. Further studies and an international consensus regarding more reproducible evaluation of regression, such as the percentage of the lesions regressed (eg, 50%), would be needed to better characterize this feature.

Moreover, this study reviewed only observational, mostly retrospective studies reported in English. Most studies were also from a single institution. In some cases, multiple reports were published over time from the same institution, and considerable effort was expended to identify and use the most suitable report. It is possible, however, that some patients were excluded by our efforts to avoid duplicates in consecutive studies reported by the same group. Nevertheless, based on the number of patients reviewed in the present analysis, it is unlikely that missing these cases would have significantly affected the results.

These limitations underscore the need for standardized reporting of relevant covariates in future observational studies. From a methodologic perspective, histologic regression needs a worldwide consensus regarding the definition to give the possibility to further analyze this intriguing feature. All other prognostic factors should also be collected accurately. It has also been recommended that 2 investigators separately assess the regression histologically in primary melanoma specimens and that high interobserver agreement should be achieved.

Conclusions

The results of this meta-analysis may be useful when deciding to offer SLNB to patients with regressions of melanomas. It may help clinicians make a final selection of the most appropriate patients for this procedure.

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Article Information

Accepted for Publication: June 12, 2015.

Corresponding Author: Simone Ribero, MD, PhD, Section of Dermatology, Department of Medical Sciences, University of Turin, Via Cherasco 23, 10100 Turin, Italy (simone.ribero@unito.it).

Published Online: September 2, 2015. doi:10.1001/jamadermatol.2015.2235.

Author Contributions: Drs Ribero and Gualano had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Ribero and Gualano contributed equally.

Study concept and design: Ribero, Gualano, Osella-Abate, Fierro, Macripò, Sapino, Siliquini.

Acquisition, analysis, or interpretation of data: Ribero, Gualano, Osella-Abate, Scaioli, Bert, Sanlorenzo, Balagna, Sapino, Quaglino.

Drafting of the manuscript: Ribero, Gualano, Osella-Abate, Scaioli, Bert, Sanlorenzo, Balagna, Sapino, Siliquini.

Critical revision of the manuscript for important intellectual content: Gualano, Fierro, Macripò, Sapino, Quaglino.

Statistical analysis: Gualano, Scaioli, Bert, Sapino.

Obtained funding: Sapino.

Administrative, technical, or material support: Balagna, Sapino.

Study supervision: Ribero, Fierro, Macripò, Sapino, Siliquini, Quaglino.

Conflict of Interest Disclosures: None reported.

References
1.
Kang  S, Barnhill  RL, Mihm  MC  Jr, Sober  AJ.  Histologic regression in malignant melanoma: an interobserver concordance study. J Cutan Pathol. 1993;20(2):126-129.
PubMedArticle
2.
Requena  C, Botella-Estrada  R, Traves  V, Nagore  E, Almenar  S, Guillén  C.  Problems in defining melanoma regression and prognostic implication [in Spanish]. Actas Dermosifiliogr. 2009;100(9):759-766.
PubMedArticle
3.
Blessing  K, McLaren  KM.  Histological regression in primary cutaneous melanoma: recognition, prevalence and significance. Histopathology. 1992;20(4):315-322.
PubMedArticle
4.
Ribero  S, Osella-Abate  S, Sanlorenzo  M,  et al.  Favourable prognostic role of regression of primary melanoma in AJCC stage I-II patients. Br J Dermatol. 2013;169(6):1240-1245.
PubMedArticle
5.
Morton  DL, Cochran  AJ, Thompson  JF,  et al; Multicenter Selective Lymphadenectomy Trial Group.  Sentinel node biopsy for early-stage melanoma: accuracy and morbidity in MSLT-I, an international multicenter trial. Ann Surg. 2005;242(3):302-311.
PubMed
6.
Lourari  S, Paul  C, Gouraud  PA,  et al; Skin Oncology Working Group of the Société Française de Dermatologie (French Society of Dermatology).  Sentinel lymph node biopsy for melanoma is becoming a consensus: a national survey of French centres involved in melanoma care in 2008. J Eur Acad Dermatol Venereol. 2012;26(10):1230-1235.
PubMedArticle
7.
Kaur  C, Thomas  RJ, Desai  N,  et al.  The correlation of regression in primary melanoma with sentinel lymph node status. J Clin Pathol. 2008;61(3):297-300.
PubMedArticle
8.
Socrier  Y, Lauwers-Cances  V, Lamant  L,  et al.  Histological regression in primary melanoma: not a predictor of sentinel lymph node metastasis in a cohort of 397 patients. Br J Dermatol. 2010;162(4):830-834.
PubMedArticle
9.
Morton  DL, Thompson  JF, Cochran  AJ,  et al; MSLT Group.  Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370(7):599-609.
PubMedArticle
10.
Ribero  S, Osella-Abate  S, Sanlorenzo  M,  et al.  Sentinel lymph node biopsy in thick-melanoma patients (N=350): what is its prognostic role? Ann Surg Oncol. 2015;22(6):1967-1973.
PubMedArticle
11.
Shaw  HM, McCarthy  SW, McCarthy  WH, Thompson  JF, Milton  GW.  Thin regressing malignant melanoma: significance of concurrent regional lymph node metastases. Histopathology. 1989;15(3):257-265.
PubMedArticle
12.
White  RL  Jr, Ayers  GD, Stell  VH,  et al; Sentinel Lymph Node Working Group.  Factors predictive of the status of sentinel lymph nodes in melanoma patients from a large multicenter database. Ann Surg Oncol. 2011;18(13):3593-3600.
PubMedArticle
13.
Balch  CM, Gershenwald  JE, Soong  SJ,  et al.  Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27(36):6199-6206.
PubMedArticle
14.
Wong  SL, Balch  CM, Hurley  P,  et al; American Society of Clinical Oncology; Society of Surgical Oncology.  Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline. J Clin Oncol. 2012;30(23):2912-2918.
PubMedArticle
15.
Panic  N, Leoncini  E, de Belvis  G, Ricciardi  W, Boccia  S.  Evaluation of the endorsement of the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement on the quality of published systematic review and meta-analyses. PLoS One. 2013;8(12):e83138.
PubMedArticle
16.
Prictor  M, Hill  S.  Cochrane Consumers and Communication Review Group: leading the field on health communication evidence. J Evid Based Med. 2013;6(4):216-220.
PubMedArticle
17.
Kuller  LH, Goldstein  BD.  Suggestions for STROBE recommendations. Epidemiology. 2007;18(6):792-793.
PubMedArticle
18.
Han  D, Zager  JS, Shyr  Y,  et al.  Clinicopathologic predictors of sentinel lymph node metastasis in thin melanoma. J Clin Oncol. 2013;31(35):4387-4393.
PubMedArticle
19.
Botella-Estrada  R, Traves  V, Requena  C, Guillen-Barona  C, Nagore  E.  Correlation of histologic regression in primary melanoma with sentinel node status. JAMA Dermatol. 2014;150(8):828-835.
PubMedArticle
20.
Grotz  TE, Vaince  F, Hieken  TJ.  Tumor-infiltrating lymphocyte response in cutaneous melanoma in the elderly predicts clinical outcomes. Melanoma Res. 2013;23(2):132-137.
PubMedArticle
21.
Testori  A, De Salvo  GL, Montesco  MC,  et al; Italian Melanoma Intergroup.  Clinical considerations on sentinel node biopsy in melanoma from an Italian multicentric study on 1,313 patients (SOLISM-IMI). Ann Surg Oncol. 2009;16(7):2018-2027.
PubMedArticle
22.
Gutzmer  R, Satzger  I, Thoms  KM,  et al.  Sentinel lymph node status is the most important prognostic factor for thick (> or = 4 mm) melanomas. J Dtsch Dermatol Ges. 2008;6(3):198-203.
PubMedArticle
23.
Morris  KT, Busam  KJ, Bero  S, Patel  A, Brady  MS.  Primary cutaneous melanoma with regression does not require a lower threshold for sentinel lymph node biopsy. Ann Surg Oncol. 2008;15(1):316-322.
PubMedArticle
24.
Topping  A, Dewar  D, Rose  V,  et al.  Five years of sentinel node biopsy for melanoma: the St George’s Melanoma Unit experience. Br J Plast Surg. 2004;57(2):97-104.
PubMedArticle
25.
Wagner  JD, Gordon  MS, Chuang  TY,  et al.  Predicting sentinel and residual lymph node basin disease after sentinel lymph node biopsy for melanoma. Cancer. 2000;89(2):453-462.
PubMedArticle
26.
Tejera-Vaquerizo  A, Nagore  E, Herrera-Acosta  E,  et al.  Prediction of sentinel lymph node positivity by growth rate of cutaneous melanoma. Arch Dermatol. 2012;148(5):577-584.
PubMedArticle
27.
Callender  GG, Egger  ME, Burton  AL,  et al.  Prognostic implications of anatomic location of primary cutaneous melanoma of 1 mm or thicker. Am J Surg. 2011;202(6):659-664.
PubMedArticle
28.
Mandalà  M, Imberti  GL, Piazzalunga  D,  et al.  Clinical and histopathological risk factors to predict sentinel lymph node positivity, disease-free and overall survival in clinical stages I-II AJCC skin melanoma: outcome analysis from a single-institution prospectively collected database. Eur J Cancer. 2009;45(14):2537-2545.
PubMedArticle
29.
Kruper  LL, Spitz  FR, Czerniecki  BJ,  et al.  Predicting sentinel node status in AJCC stage I/II primary cutaneous melanoma. Cancer. 2006;107(10):2436-2445.
PubMedArticle
30.
Liszkay  G, Orosz  Z, Péley  G,  et al.  Relationship between sentinel lymph node status and regression of primary malignant melanoma. Melanoma Res. 2005;15(6):509-513.
PubMedArticle
31.
Savoia  P, Fava  P, Caliendo  V,  et al.  Disease progression in melanoma patients with negative sentinel lymph node: does false-negative specimens entirely account for this phenomenon? J Eur Acad Dermatol Venereol. 2012;26(2):242-248.
PubMedArticle
32.
Ribero  S, Quaglino  P, Osella-Abate  S,  et al.  Relevance of multiple basin drainage and primary histologic regression in prognosis of trunk melanoma patients with negative sentinel lymph nodes. J Eur Acad Dermatol Venereol. 2013;27(9):1132-1137.
PubMedArticle
33.
Ma  MW, Medicherla  RC, Qian  M,  et al.  Immune response in melanoma: an in-depth analysis of the primary tumor and corresponding sentinel lymph node. Mod Pathol. 2012;25(7):1000-1010.
PubMedArticle
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